The HDAC inhibitor valproate induces a bivalent status of the CD20 promoter in CLL patients suggesting distinct epigenetic regulation of CD20 expression in CLL in vivo

ZL277 is a prodrug of belinostat with enhanced bioavailability and efficacy as a pan histone deacetylase (HDAC) inhibitor. In this study, we investigated the metabolism and pharmacokinetics of ZL277 in liver S9 fractions, liver microsomes, liver cytosol, and in mice. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem mass spectrometry. The in vitro metabolic profile of ZL277 includes ZL277-B(OH)2-452, the major oxidative metabolite ZL277-OH-424, the active ingredient belinostat, belinostat amide, belinostat acid, and methylated belinostat in liver S9 fractions. Both ZL277-OH-424 and belinostat underwent further glucuronidation in liver microsome, whereas only ZL277-OH-424, but not belinostat, underwent some level of sulfation in rat liver cytosols. These metabolites were examined in plasma and in a breast tumor model in vivo. They were also examined in urine and feces from mice treated with ZL277. The pharmacokinetic study of ZL277 showed the parameters of active drug belinostat with a half-life (t1/2) of 10.7 h, an area under curve value (AUC) of 1506.9 ng/mL*h, and a maximum plasma concentration (Cmax) of 172 ng/mL, reached 3 h after a single dose of 10 mg/kg. The hydrolysis product of the prodrug, ZL277-B(OH)2-452 showed an AUC of 8306 ng/mL*h and Cmax of 931 ng/mL 3 h after drug administration.

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Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells

Frontiers in Oncology ◽

10.3389/fonc.2021.723966 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jane L. Roberts ◽

Laurence Booth ◽

Andrew Poklepovic ◽

Paul Dent

Keyword(s):

Hdac Inhibitor ◽

Kinase Inhibitor ◽

Hdac Inhibitors ◽

Autophagic Flux ◽

Drug Induced ◽

Ampk Signaling ◽

Knock Down ◽

Reduce Tumor Growth ◽

Sarcoma Cells

We have extended our analyses of HDAC inhibitor biology in sarcoma. The multi-kinase inhibitor axitinib interacted with multiple HDAC inhibitors to kill sarcoma cells. Axitinib and HDAC inhibitors interacted in a greater than additive fashion to inactivate AKT, mTORC1 and mTORC2, and to increase Raptor S722/S792 phosphorylation. Individually, all drugs increased phosphorylation of ATM S1981, AMPKα T172, ULK1 S317 and ATG13 S318 and reduced ULK1 S757 phosphorylation; this correlated with enhanced autophagic flux. Increased phosphorylation of ULK1 S317 and of Raptor S722/S792 required ATM-AMPK signaling. ULK1 S757 is a recognized site for mTORC1 and knock down of either ATM or AMPKα reduced the drug-induced dephosphorylation of this site. Combined exposure of cells to axitinib and an HDAC inhibitor significantly reduced the expression of HDAC1, HDAC2, HDAC3, HDAC4, HDAC6 and HDAC7. No response was observed for HDACs 10 and 11. Knock down of ULK1, Beclin1 or ATG5 prevented the decline in HDAC expression, as did expression of a constitutively active mTOR protein. Axitinib combined with HDAC inhibitors enhanced expression of Class I MHCA and reduced expression of PD-L1 which was recapitulated via knock down studies, particularly of HDACs 1 and 3. In vivo, axitinib and the HDAC inhibitor entinostat interacted to significantly reduce tumor growth. Collectively our findings support the exploration of axitinib and HDAC inhibitors being developed as a novel sarcoma therapy.

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Antagonistic interaction between Ezh2 and Arid1a coordinates root patterning and development via Cdkn2a in mouse molars

eLife ◽

10.7554/elife.46426 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Junjun Jing ◽

Jifan Feng ◽

Jingyuan Li ◽

Xia Han ◽

Jinzhi He ◽

...

Keyword(s):

Epigenetic Regulation ◽

Root Development ◽

Physiological Function ◽

Tooth Root ◽

Tooth Regeneration ◽

Jaw Bones ◽

Antagonistic Interaction ◽

Tooth Type ◽

Epigenetic Regulators

Patterning is a critical step during organogenesis and is closely associated with the physiological function of organs. Tooth root shapes are finely tuned to provide precise occlusal support to facilitate the function of each tooth type. However, the mechanism regulating tooth root patterning and development is largely unknown. In this study, we provide the first in vivo evidence demonstrating that Ezh2 in the dental mesenchyme determines patterning and furcation formation during dental root development in mouse molars. Mechanistically, an antagonistic interaction between epigenetic regulators Ezh2 and Arid1a controls Cdkn2a expression in the dental mesenchyme to regulate dental root patterning and development. These findings indicate the importance of balanced epigenetic regulation in determining the tooth root pattern and the integration of roots with the jaw bones to achieve physiological function. Collectively, our study provides important clues about the regulation of organogenesis and has general implications for tooth regeneration in the future.

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Synergistic Interaction between the HDAC Inhibitor, MPT0E028, and Sorafenib in Liver Cancer Cells In Vitro and In Vivo

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-12-3909 ◽

2014 ◽

Vol 20 (5) ◽

pp. 1274-1287 ◽

Cited By ~ 31

Author(s):

Chun-Han Chen ◽

Mei-Chuan Chen ◽

Jing-Chi Wang ◽

An-Chi Tsai ◽

Ching-Shih Chen ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Hdac Inhibitor ◽

Synergistic Interaction ◽

Liver Cancer Cells

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Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00030-12 ◽

2012 ◽

Vol 56 (7) ◽

pp. 3849-3856 ◽

Cited By ~ 55

Author(s):

Subathdrage D. M. Sumanadasa ◽

Christopher D. Goodman ◽

Andrew J. Lucke ◽

Tina Skinner-Adams ◽

Ishani Sahama ◽

...

Keyword(s):

Cerebral Malaria ◽

Histone Deacetylase ◽

Hdac Inhibitor ◽

Antimalarial Activity ◽

Hdac Inhibitors ◽

Parasite Life Cycle ◽

Nonhistone Proteins ◽

Content Type

ABSTRACTHistone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, thein vitroandin vivoantiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth ofPlasmodium falciparumasexual-stage parasitesin vitro(50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited thein vitrogrowth of exoerythrocytic-stagePlasmodiumparasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimentalin vivomurine model of cerebral malaria, orally administered SB939 significantly inhibitedP. bergheiANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

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In vitro and in vivo anti-uveal melanoma activity of JSL-1, a novel HDAC inhibitor

Cancer Letters ◽

10.1016/j.canlet.2017.04.028 ◽

2017 ◽

Vol 400 ◽

pp. 47-60 ◽

Cited By ~ 15

Author(s):

Yun Wang ◽

Maoxing Liu ◽

Yanli Jin ◽

Sheng Jiang ◽

Jingxuan Pan

Keyword(s):

Uveal Melanoma ◽

Hdac Inhibitor

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